Newborn screening (NBS) is an essential public health program in all 50 states. The falling cost of whole genome/ exome sequencing provides an opportunity to ask whether whole genome analysis (WGA) might serve as a method of cost-effective newborn screening for any and every condition. We will address certain critical questions raised by the application of this technology to NBS. We will use Whole Exome Sequencing (WES) as a cost-effective method of WGA in 1620 newborn blood spots that are linked to the clinical data of the newborns. We will then test WES as a NBS Tool for metabolic and immunological disorders. These data will be used to 1) compare the sensitivity and specificity of mutation data with biochemical testing, 2) identify gene variants that predict which children with certain metabolic disorders are at greater risk for metabolic decompensation, 3) identify mutations in genes responsible for those primary immunodeficiencies that are not detected by the current T-Cell receptor excision circle assay used for severe combined immunodeficiency screening, and 4) scan 9 genes for variants that are clinically important for drug metabolism and would be typical secondary findings if WES were to be used as a NBS method. We will also develop a participant protection framework for conducting WGA during the neonatal period, determine the views, perspectives, and value preferences of key stakeholders about using WGA for NBS, collaborate with the UC Hastings Consortium on Law, Science and Health Policy, to identify the legal and constitutional issues for using WGA, and for incorporating PGx into NBS programs, and develop and disseminate policy recommendations for expanded NBS programs based on WGA. RELEVANCE: We plan to test the use of one method of whole genome analysis, whole exome sequencing, as the sole method of newborn screening for disorders currently being screened for and others that are missed by current newborn screening but for which newborn screening might be appropriate. This would provide substantial public health benefit for newborns who might otherwise go undiagnosed and untreated while serious, even irreversible, damage occurs. Equally important, we will explore parents' interest in incidental findings and develop appropriate legal frameworks to make sure NBS by WGA can be done ethically.